Ketamine plus psychotherapy pairings

1. Introduction

Version followed: this is not a single named therapy but a family of research pairings. The guide follows six published protocols: (1) Yale CBT after ketamine for treatment-resistant depression (Wilkinson et al., pilot 2017; randomised trial 2021), with the esketamine follow-on CBT-ENDURE; (2) Columbia EX/RP after ketamine for OCD (Rodriguez et al., 2016); (3) Yale massed prolonged exposure with ketamine (Harpaz-Rotem, NCT02727998); (4) Minneapolis VA ketamine-enhanced prolonged exposure (Shiroma, NCT04560660); (5) KARE, ketamine with mindfulness-based relapse-prevention therapy for alcohol use disorder (Grabski, Morgan et al., Exeter/UCL), and its phase III successor MORE-KARE (ISRCTN85955128); (6) NYSPI motivational enhancement therapy (MET) with a ketamine session for alcohol use disorder (Dakwar, NCT02539511). Each pairing uses the therapist's ordinary evidence-based manual (Beck CBT, Foa EX/RP, Foa PE, MBRP, MET), timed around ketamine sessions that a medical team runs.

What it is: a psychotherapist delivers a standard structured therapy in a planned relationship to ketamine or esketamine sessions run by medical staff. The ketamine is not the therapy. Here it is used as a possible "enhancer" or "facilitator" of the psychotherapy, unlike the psychedelic-style ketamine-assisted psychotherapy models in other tabs of this family. [source: Wilkinson 2021; NCT04560660 protocol; NCT02727998 protocol]

Core idea of change (hypotheses, per the authors): ketamine may open a time-limited "window" of increased neuroplasticity and flexible learning. Therapy placed in that window may consolidate new learning faster: extinction in exposure, new appraisals and activity patterns in CBT, motivation to change in MET, relapse-prevention skills in MBRP. Ketamine's rapid symptom relief may also lower anticipatory fear and hopelessness, which may reduce early dropout and help engagement. The protocols call these mechanisms hypotheses, not established findings. [source: Wilkinson 2021; NCT04560660; NCT02727998; NCT02539511] In KARE and the VA PE pilot, the therapy's added contribution over ketamine alone was not confirmed. [source: Grabski et al. KARE manuscript; NCT04560660]

Scope rule for this guide: there are no doses, routes, infusion details or drug schedules. Everything medical (prescribing, administering, physiological monitoring, discharge decisions) belongs to the medical team and is named here only as their responsibility. [synthesis, per house rule]

2. Framework

Common architecture across the pairings [source: all six protocols; the cross-protocol summary is synthesis]

1. Medical and psychiatric screening (medical team, with the therapist contributing). Eligibility follows published exclusion criteria (see below).
2. Therapy engagement and preparation. This is the first therapy session(s): rationale, goals, treatment planning, preparation for possible drug-session experiences.
3. Ketamine-paired phase. Therapy sessions are placed before and/or after the medical team's ketamine sessions, as the protocol specifies. The psychological work is done when the acute drug effects have worn off, not during them (VA PE protocol: no psychological intervention or directives while acute effects are active). The exception is supportive presence and mindfulness/relaxation guidance during the session in KARE and the NYSPI MET protocol.
4. Medication-free continuation phase (CBT, PE). The manualised therapy continues to completion without further ketamine.
5. Termination and relapse prevention, then follow-up assessments.

Pairing-by-pairing format

Criteria for moving between phases

• Into the paired phase: eligibility confirmed by the medical team, informed consent, and (alcohol protocols) initial abstinence verified (KARE: at least 24 h abstinent with breath alcohol zero; MET: not intoxicated and not in moderate withdrawal; otherwise rescheduled within a week). [source: KARE; NCT02539511]
• Into CBT (Yale): response to the ketamine phase is the gate. Non-responders were not randomised. [source: Wilkinson 2021]
• Into imaginal exposure (VA PE): sessions 1–2 complete (rationale, breathing, psychoeducation, in vivo hierarchy). Imaginal exposure starts in session 3. [source: NCT04560660]
• Early ending of PE: the VA pilot ended PE after 7 sessions for 3 of 7 participants when therapist and participant agreed goals were met. [source: NCT04560660]
• Discontinuation / review triggers (medical team decides): clinical deterioration (VA: a 25% rise in PCL-5 or CAPS-5, CGI ≥6, or increased suicidality, which prompt investigator review rather than automatic withdrawal), intolerable adverse effects, psychosis or persistent dissociation (removed and referred, NYSPI), pregnancy, problematic substance use, new cardiovascular symptoms or blood pressure above threshold. [source: NCT04560660; NCT02539511]

Eligibility and exclusions the protocols publish (therapist should know them)

• Common exclusions: psychotic disorders (current or past, including substance-induced in MORE-KARE; family history of psychosis in NYSPI); bipolar disorder or antidepressant-induced mania; current serious suicide risk or attempt in the past year (NYSPI, MORE-KARE); ketamine misuse or ketamine use disorder; other significant substance dependence (varies by protocol); pregnancy or breastfeeding; uncontrolled hypertension and unstable cardiac, hepatic, renal or CNS conditions; moderate-severe TBI or cognitive impairment (PE protocols). [source: KARE; ISRCTN85955128; NCT02539511; NCT04560660; NCT02727998]
• Protocol-specific exclusions: dissociative disorders or a high dissociation score (NYSPI MET); borderline personality disorder and OCD (Yale massed PE); prior PE (VA); severe depression and current CBT (Columbia OCD); antidepressant or antihypertensive use and more than ten inpatient detoxes (KARE phase II); BMI outside protocol limits (NYSPI, MORE-KARE). [same sources]

Legal and regulatory status (as of the sources' dates)

• United States: esketamine (Spravato) is FDA-approved for adults with treatment-resistant depression and for depressive symptoms in MDD with acute suicidal ideation or behaviour. It is Schedule III and available only under the Spravato REMS: enrolled providers, use in a certified healthcare setting, and post-administration monitoring by staff who can complete the required assessments. [source: CBH Spravato procedures, Oct 2025] A January 2025 FDA approval of esketamine as monotherapy was reported (Healio headline) [uncertain]. Racemic ketamine has no psychiatric indication, so psychiatric use is off-label. In all the US trials here it was given under IND/IRB research conditions. [source: protocols; off-label status is synthesis]
• United Kingdom: esketamine was licensed for TRD (December 2019) and is a Schedule 2 controlled drug with a mandatory patient register (from April 2022). The Scottish Medicines Consortium accepted it (2020). NICE did not recommend it (TA854, 2022). Racemic ketamine is unlicensed for depression; a few NHS trusts use it off-label and private clinics exist. [source: Pharmaceutical Journal, Sept 2023] MORE-KARE is a UK phase III NIHR-funded trial, recruiting from 2024 with completion listed for 2027. [source: ISRCTN85955128]
• EU: esketamine has an EMA assessment (2019). The conditions of use are not described in the sources [uncertain].
• Implication for the therapist: these pairings exist in research protocols. Outside trials, a therapist can offer the same psychotherapy alongside lawful esketamine (REMS) or off-label ketamine prescribed by a physician, with a written agreement on roles. The therapist never supplies, sources or administers the drug. [synthesis]

Team roles

• Medical team (prescriber/PI, study physician or psychiatrist, research nurse, anaesthetist where used): screening exams, labs and ECG, pre-session safety questions, administration, vital signs, dissociation/psychotomimetic/mania ratings during the session, discharge readiness, 24-hour on-call cover, adverse-event grading and reporting. [source: NCT04560660; NCT02727998; NCT02539511; KARE]
• Therapist: delivers the manualised therapy. Depending on protocol, the therapist also prepares the client, gives supportive presence (KARE) or mindfulness-based relaxation as a "sitter" (NYSPI) during the session, and debriefs. Therapists were licensed doctoral or master's psychologists (VA), Beck Institute-certified CBT therapists (Yale CBT), trained psychologists delivering both arms (KARE), and MET-trained therapists supervised by the PI (NYSPI). [same sources; Wilkinson 2021]
• Fidelity: recorded sessions reviewed by a certified PE trainer, with independent fidelity rating of about 10% of sessions (VA). KARE had weekly or fortnightly review of recordings by an independent consultant clinical psychologist and a scripted step-by-step guidebook for therapist and participant. [source: NCT04560660; KARE]

3. Guiding principles

[source: derived from the six protocols as cited; one-line practical meanings are synthesis unless cited]

• The manual is the treatment; ketamine is an adjunct. Deliver Beck CBT, Foa EX/RP or PE, MBRP or MET with normal fidelity. Do not invent "ketamine versions" of techniques. [source: Rodriguez 2016 "standard procedures"; NCT04560660]
• Do psychological work after the acute effects, not during them. Schedule exposure, restructuring and MET in the post-session window the protocol defines. During the acute phase, offer only support or simple relaxation where the protocol allows it. [source: NCT04560660; KARE; NCT02539511]
• Use the window deliberately. Front-load the most learning-dependent work (hierarchy work and early exposures, first BA plans) into the protocol's paired phase. [source: NCT04560660 "priming"; Rodriguez 2016; synthesis]
• Mechanisms are hypotheses: say so. Tell clients that the "plasticity window" is a research idea, not a promise. [source: Wilkinson 2021]
• Medical safety belongs to the medical team. Never decide on drug sessions, monitoring or discharge. Report risk, side effects and deterioration to the prescriber at once. [source: NCT04560660; NCT02539511]
• Bracket each drug session with therapy. Prepare before and integrate after, so the experience links to the client's treatment goals (KARE: recall the previous therapy session and the intention for a life without alcohol). [source: KARE]
• Rapid relief is an opportunity and a risk. Use early improvement to build engagement and skills. Plan for possible return of symptoms when ketamine stops. The Yale CBT rationale was to sustain response and reduce the need for ongoing ketamine. [source: Wilkinson 2021]
• Measure every session. Use SUDS in exposure, PHQ-9 every other session (VA), C-SSRS at set points, and the protocol's symptom scale (Y-BOCS, CAPS-5/PCL-5, MADRS/QIDS, drinking measures). [source: NCT04560660; Rodriguez 2016; Wilkinson 2021]
• Suicide risk is monitored continuously. Severe depression populations had serious adverse events related to worsening depression or suicidality in both arms. [source: Wilkinson 2021]
• Abstinence and sobriety are preconditions in the addiction pairings. Verify, and reschedule rather than proceed when the client is intoxicated or in withdrawal. [source: KARE; NCT02539511]
• Watch for misuse. Ketamine misuse history is an exclusion. Some KARE participants used ketamine recreationally during follow-up, so ask about it routinely. [source: KARE]
• Match contact time when comparing. Trials matched the control (alcohol education) for contact time. In practice, the lesson is that relationship and contact are active ingredients you must deliver well. [source: KARE; practical reading is synthesis]

4. Intervention inventory

Organisation: A = frame procedures shared across pairings; B = CBT for depression; C = EX/RP for OCD; D = prolonged exposure for PTSD; E = KARE MBRP-based therapy for alcohol; F = MET for alcohol. Each manual's own content (Beck, Foa, MBRP, Miller) is paraphrased, not reproduced. Where a ketamine protocol only says "standard procedures", the steps given are standard practice for that manual, marked [synthesis].

A1. Therapist's part in screening and eligibility

• Purpose / when: before any ketamine-paired work. The therapist adds a psychological picture to the medical team's screening.
• Steps: (1) Get the protocol's exclusion list from the prescriber (Section 2). (2) Assess psychiatric history for psychosis (personal and, per NYSPI, family), bipolar or past antidepressant-induced mania, dissociative symptoms (NYSPI excluded high dissociation scores), current suicide risk with a structured tool (C-SSRS was used in the VA protocol), substance use including any past ketamine misuse, and personality-disorder features where relevant (Yale massed PE excluded borderline personality disorder). (3) Confirm the target diagnosis and baseline severity with the protocol's measure (Y-BOCS, CAPS-5/PCL-5, MADRS/QIDS, drinking timeline). (4) Confirm willingness to do the full therapy, not just the drug sessions (VA required voluntary willingness to do PE). (5) Write a summary to the prescriber, flagging anything uncertain. The medical team decides. [source: NCT04560660; NCT02539511; NCT02727998; Rodriguez 2016]
• Example language (illustrative): "Part of my job is to check whether this combination is a safe fit for you. Some of these questions are about experiences like losing touch with reality or feeling unreal, because those matter for ketamine."
• Watch for: clients who minimise psychotic-like or dissociative experiences, or past ketamine use, in order to qualify. Clients who want only the drug. Working: a clear, documented eligibility decision that the client understands.

A2. Informed consent and expectation setting

• Purpose / when: before the paired phase. Repeat briefly before each drug session.
• Steps: (1) Explain the division of roles (medical team vs therapist). (2) Explain the rationale as a hypothesis: possible learning window plus possible early relief. (3) Explain the main effects the medical team will monitor (sedation, dissociation, perceptual change, blood-pressure rise) in general terms, and say that the prescriber gives the medical consent. (4) Explain that therapy continues after the drug sessions and is the part expected to make change last. (5) Explain monitoring, discontinuation triggers and the right to withdraw at any time. (6) Explain practical rules the team sets (no driving afterwards, someone to accompany them home where required). [source: role division and withdrawal from NCT04560660, NCT02539511; REMS setting from CBH document; wording and sequence are synthesis]
• Example language (illustrative): "The researchers think ketamine may make the next days a good time to learn new patterns, but that's still being tested. What we know works is the therapy, so we'll put real effort into the sessions after."
• Watch for: belief that ketamine alone will cure. Pressure to consent because of desperation (TRD, suicidality). Working: the client can restate the plan and the roles.

A3. Preparation session before a drug session

• Purpose / when: before each drug session (KARE: a therapy session before each drug session; NYSPI: relaxation and psychological preparation on the day). [source: KARE; NCT02539511]
• Steps (KARE version): (1) Describe the range of possible experiences in general terms (altered perception, floating or detached feelings, emotional shifts) and that they pass. (2) Explain how to use the experience: reflect on the preceding therapy session's theme. (3) Rehearse the relaxation or mindfulness technique learned earlier as the coping tool if anxious. (4) Invite the client, where possible, to bring their intention to mind (in KARE, an intention for a life without alcohol). (5) Explain the setting: single room, headphones with instrumental music, therapist, psychologist and nurse present. [source: KARE]
• Example language (illustrative): "If things feel strange, that's expected and it passes. Come back to the breathing we practised. If you can, hold in mind what you want your life without drinking to look like."
• Watch for: high anticipatory anxiety (rehearse the coping skill more). Unrealistic or spiritualised expectations (re-anchor to the treatment goal). Working: the client can name the intention and the coping tool.

A4. Supportive presence or mindfulness "sitting" during the drug session

• Purpose / when: only in protocols that put a therapist in the room (KARE: therapist present throughout for reassurance; NYSPI: a trained sitter gives mindfulness-based relaxation). In the VA PE protocol, no psychological intervention or directives are given while acute effects are active. Follow your protocol. [source: KARE; NCT02539511; NCT04560660]
• Steps: (1) Sit quietly within the client's sight. (2) Respond to distress with brief reassurance and an invitation to the practised breathing or body-awareness exercise. (3) Do not do exposure, restructuring, interpretation or new content. (4) Leave vital signs, side-effect ratings and any physical care to the nurse and physician. Alert them at once to any physical or psychiatric concern. (5) Keep conversation minimal. Music and headphones are the main environment in KARE. [source: KARE; NCT02539511; steps 1–3 detail is synthesis]
• Touch: the sources state no touch policy [uncertain]. A conservative default is no touch beyond what was agreed in advance in writing [synthesis].
• Example language (illustrative): "You're safe, I'm here. Notice your breath going in and out… the feeling will change."
• Watch for: panic, paranoid ideation, marked agitation or confusion. Report to medical staff; the physician decides. Working: the client settles with minimal input.

A5. Post-session debrief and integration

• Purpose / when: after each drug session. KARE holds a therapy (or education) session the day after each drug session. NYSPI holds a MET session before discharge. Yale massed PE has a clinician debrief each test day. [source: KARE; NCT02539511; NCT02727998]
• Steps: (1) Check in on current state and any lingering effects. Escalate persistent dissociation or perceptual change to the physician (NYSPI removes and refers participants with psychosis or persistent dissociation). (2) Invite the client to describe what came up, briefly. (3) Link insights or emotions to the therapy's goals (intention, hierarchy item, values). (4) Translate them into a concrete next step or homework in the host therapy. (5) Note mood changes, including euphoria or low mood (both occurred as severe adverse events in KARE), and report. [source: KARE; NCT02539511; linking steps 2–4 are synthesis]
• Example language (illustrative): "What from yesterday seems most relevant to what you're working on? Let's turn that into one thing to practise this week."
• Watch for: the client over-valuing the drug experience at the expense of skills. Distressing material. Working: a homework task that grows out of the session.

A6. Session-by-session measurement and safety monitoring

• Purpose / when: throughout.
• Steps: (1) Give the protocol's primary measure at the set points. (2) Take SUDS (0–100) during each exposure. (3) PHQ-9 every other session (VA practice). (4) C-SSRS at baseline, during treatment and follow-up. (5) Compare with the deterioration thresholds (VA: 25% rise in PCL-5/CAPS-5, CGI ≥6, increased suicidality) and refer to the investigator/prescriber when they are crossed. [source: NCT04560660]
• Watch for: worsening after ketamine sessions stop (the reason the Yale CBT trial existed). Working: steady or improving scores during the medication-free phase.

B1. CBT psychoeducation (Yale, Beck model)

• Purpose / when: opening sessions of the CBT phase, after response to ketamine. [source: Wilkinson 2021]
• Steps: (1) Explain the cognitive model: situations, thoughts, emotions, behaviours and body sensations interact. (2) Link it to the client's own recent example. (3) Frame the recent improvement as a chance to learn skills that keep it going. (4) Set goals. [source: Beck-model psychoeducation named in Wilkinson 2021; step content is standard Beck CBT, synthesis]
• Example language (illustrative): "You're feeling better right now. Let's use that energy to learn how your thoughts and actions keep depression going or keep it away."
• Watch for: the client crediting all gains to ketamine and seeing no need for CBT. Working: the client can map one episode onto the model.

B2. Structured session format: agenda, homework review, new homework

• Purpose / when: every CBT session. [source: Wilkinson 2021]
• Steps: (1) Mood check with the measure. (2) Set a collaborative agenda. (3) Review last session's homework (activity chart or thought record). (4) Work on one or two agenda items. (5) Assign new homework and anticipate obstacles. (6) Summarise and get feedback. [source: agenda, homework review and assignment from Wilkinson 2021; steps 1, 5–6 standard Beck structure, synthesis]
• Example language (illustrative): "What would be most useful to put on today's agenda? And let's start by looking at how the activity chart went."
• Watch for: homework not done. Address it first (Section 5). Working: homework completed and discussed most weeks.

B3. Behavioural activation with activity charts

• Purpose / when: early CBT phase, especially when anhedonia or withdrawal persists. [source: Wilkinson 2021]
• Steps: (1) Monitor activity and mood hour by hour on an activity chart. (2) Rate pleasure and mastery. (3) Identify links between activity and mood. (4) Schedule graded valued activities. (5) Review and adjust. [source: activity charts named in Wilkinson 2021; steps are standard BA, synthesis]
• Example language (illustrative): "Let's pick two activities this week that used to give you a sense of achievement, and make the first step small enough that you'd do it even on a bad day."
• Watch for: over-scheduling while energy is high after ketamine, then crashing. Working: increased activity and mood ratings that track it.

B4. Cognitive restructuring with thought records

• Purpose / when: once the client can name thoughts; across the CBT phase. [source: Wilkinson 2021]
• Steps: (1) Identify a situation and the emotion with its intensity. (2) Catch the automatic thought. (3) Examine the evidence for and against it, and alternatives. (4) Form a balanced thought. (5) Re-rate the emotion. (6) Practise between sessions with the thought record. Later, look for recurring themes and core beliefs. [source: thought records named in Wilkinson 2021; steps standard Beck CBT, synthesis]
• Example language (illustrative): "When you thought 'the improvement won't last', how strongly did you believe it? What's the evidence on both sides?"
• Watch for: fear of relapse once ketamine ends. Hopelessness and suicidal thoughts (monitor; Section 5). Working: lower belief ratings and quicker self-correction.

B5. Relapse prevention at CBT end

• Purpose / when: final sessions. [uncertain: the 2021 paper does not describe a relapse-prevention module; included as standard CBT practice, synthesis]
• Steps: (1) Review the skills that helped. (2) List early warning signs. (3) Write a personal plan, including when to contact the prescriber. (4) Schedule booster contacts if available.
• Example language (illustrative): "What are the first signs that depression is creeping back for you, and what will you do on day one?"
• Watch for: dependence on the therapist or on further ketamine as the only plan.

C1. EX/RP treatment-planning session (before ketamine)

• Purpose / when: the longer planning session before ketamine in the Columbia protocol, so exposure can start at once in the post-ketamine window. [source: Rodriguez 2016]
• Steps: (1) Map obsessions, feared consequences, and overt and covert rituals and avoidance. (2) Explain the EX/RP rationale: facing triggers without rituals lets anxiety decline and teaches that feared outcomes don't occur or can be tolerated. (3) Build a graded exposure hierarchy with SUDS ratings. (4) Agree response-prevention rules. (5) Plan the first exposures. [source: Rodriguez 2016 says sessions followed standard Foa, Yadin & Lichner procedures; specific steps are standard EX/RP practice, synthesis; the manual is not drawn on, uncertain]
• Example language (illustrative): "Over the next two weeks we'll work intensively. Let's rank the situations you avoid from easiest to hardest so we're ready to begin straight away."
• Watch for: hidden or mental rituals left off the list. Working: a complete hierarchy and agreed rules.

C2. In-session exposure (post-ketamine, intensive)

• Purpose / when: the 10 one-hour sessions over 2 weeks after ketamine. [source: Rodriguez 2016]
• Steps: (1) Start with a moderate hierarchy item. (2) The client engages with the trigger fully, without neutralising. (3) Rate SUDS at regular intervals. (4) Stay until distress falls noticeably or the learning goal is met. (5) Discuss what was learned. (6) Move up the hierarchy across sessions, reaching top items before the end. [synthesis: standard EX/RP; not specified in the ketamine report]
• Example language (illustrative): "Touch the doorhandle and keep your hand there. What's your anxiety now, 0 to 100? What does your OCD say will happen?"
• Watch for: subtle avoidance (looking away, mental reassurance). Working: falling peak SUDS and the client choosing harder items. Y-BOCS was the outcome measure (response defined as at least 35% reduction). [source: Rodriguez 2016]

C3. Response prevention and between-session exposure homework

• Purpose / when: throughout the intensive phase. [synthesis: standard EX/RP]
• Steps: (1) Agree written rules for which rituals to stop and for how long. (2) Plan daily self-directed exposures. (3) Log urges and slips. (4) Review the log at the next session.
• Example language (illustrative): "When the urge to check comes, note it, rate it, and see what happens if you let it be there without checking."
• Watch for: reassurance-seeking from family. Ritual substitution. Working: fewer rituals and a falling time cost of obsessions.

C4. Planning for after the intensive window

• Purpose / when: at the end of the 2 weeks. Gains faded between weeks 2 and 4 in the Columbia pilot (mean Y-BOCS reduction 10.75 at week 2 vs 6.88 at week 4). [source: Rodriguez 2016]
• Steps: (1) Write a self-exposure plan for continued practice. (2) Arrange continued EX/RP or a referral. (3) Teach the client to spot early ritual creep. [synthesis]
• Example language (illustrative): "The gains need practice to hold. Let's set up your next four weeks of exposures now."
• Watch for: stopping all exposures once acute relief fades.

D1. PE session 1: rationale, information gathering, breathing retraining

• Purpose / when: first PE session. In the VA protocol it follows the first ketamine session. [source: NCT04560660]
• Steps: (1) Explain the treatment programme and the rationale (avoidance maintains PTSD; emotional processing reduces it). (2) Gather trauma history and identify the index trauma. (3) Teach slow breathing retraining as a calming skill. (4) Assign breathing practice. [source: NCT04560660; NCT02727998]
• Example language (illustrative): "Avoiding the memories and reminders makes sense in the short term, but it keeps the fear alive. This programme helps you approach them safely, step by step."
• Watch for: the client experiencing breathing as a way to avoid. Present it as a general calming skill, not a tool to use during exposure. [synthesis]

D2. PE session 2: common trauma reactions and in vivo hierarchy

• Purpose / when: second session. [source: NCT04560660]
• Steps: (1) Discuss common reactions to trauma and normalise the client's symptoms. (2) Explain the rationale for in vivo exposure. (3) Build a hierarchy of avoided situations that are objectively safe or low risk, rated by SUDS. (4) Set graded in vivo homework. The Yale massed version starts by identifying 3–5 avoidance behaviours in session 1. [source: NCT04560660; NCT02727998]
• Example language (illustrative): "Which places or activities have you stopped doing since the trauma, even though they're actually safe?"
• Watch for: items that are genuinely unsafe (exclude them). Working: a 10–15 item hierarchy and completed first homework.

D3. Imaginal exposure

• Purpose / when: from session 3 (VA). In the massed Yale format it runs through sessions 3–6. [source: NCT04560660; NCT02727998]
• Steps: (1) Explain the rationale. (2) With eyes closed if possible, the client recounts the trauma aloud in the present tense, including thoughts, feelings and sensations. (3) The therapist prompts for detail and SUDS ratings at intervals. (4) Repeat the account within the session, aiming for sustained engagement (session 3 targets 45–60 minutes of reliving; later sessions 30–45 minutes). (5) In later sessions, focus on "hot spots". (6) Record the session so the client can listen daily. [source: NCT04560660; hot-spot step is standard PE, synthesis]
• Example language (illustrative): "Tell me what's happening now, as if it's happening. What do you see? What are you feeling in your body?"
• Watch for: under-engagement (flat, past tense, skipping) or over-engagement (dissociation, losing contact with the room). Adjust (Section 5). Working: SUDS habituation within and across sessions.

D4. Processing after imaginal exposure

• Purpose / when: immediately after each imaginal exposure. [source: NCT04560660]
• Steps: (1) Ask open questions about what the client noticed. (2) Explore meanings, such as self-blame, danger beliefs and incompetence. (3) Highlight new perspectives that emerge. (4) Validate. [source: "processing" named in NCT04560660; content is standard PE, synthesis]
• Example language (illustrative): "Going through it again today, what stood out? You said 'I should have known'. How does that look to you now?"
• Watch for: the therapist arguing or lecturing. Working: the client spontaneously revising appraisals.

D5. Homework review and in vivo/imaginal homework

• Purpose / when: every session from session 3. [source: NCT04560660; NCT02727998]
• Steps: (1) Review the in vivo log and the listening log with SUDS. (2) Problem-solve barriers. (3) Assign the next in vivo items and daily recording listening.
• Example language (illustrative): "What happened to your distress the third time you went to the supermarket compared with the first?"
• Watch for: avoidance of listening to recordings. Working: decreasing SUDS for hierarchy items.

D6. Final session: summary, progress review and relapse prevention

• Purpose / when: last session (session 10, or earlier if goals are met by agreement). [source: NCT04560660]
• Steps: (1) Do a final shortened imaginal exposure where standard practice calls for it [synthesis]. (2) Re-rate the hierarchy. (3) Review learning and progress. (4) Plan continued self-exposure and future goals. (5) Address relapse prevention. [source: NCT04560660]
• Example language (illustrative): "Let's look at your first hierarchy ratings and what they are today. What will you keep practising?"
• Watch for: residual avoidance items. Working: CAPS-5/PCL-5 improvement.

D7. Massed PE variant (Yale)

• Purpose / when: intensive one-week format with ketamine sessions within the week. [source: NCT02727998]
• Steps: (1) Session 1: assessment, trauma review, identify 3–5 avoidance behaviours. (2) Session 2: psychoeducation (about 30 minutes), then about 90 minutes of PE after the client has recovered from any study-drug session that day. (3) Sessions 3–6: about 90-minute PE sessions with imaginal and in vivo work. (4) Session 7: final PE session and exit interview. (5) Follow-up visits at about 1–2 months. (6) Optional skin-conductance monitoring during sessions in research. [source: NCT02727998]
• Example language (illustrative): "This week is intensive by design. Each day builds on the one before, so the homework between sessions matters a lot."
• Watch for: fatigue. Contact by staff at 24 hours, one week and one month after the last drug session was built in. [source: NCT02727998]

E1. KARE session structure (two themes per session)

• Purpose / when: all seven KARE therapy sessions, about 1.5 h each, starting at the second visit. [source: KARE]
• Steps: (1) Check in and review journal and home practice. (2) Work on one topic from the relapse-prevention theme. (3) Work on one topic from the wellbeing theme (building an enjoyable, meaningful life without alcohol). (4) Teach and practise that session's relaxation or mindfulness exercise (a different one each session). (5) Set journal and home practice. (6) Follow the scripted participant and therapist guidebook for adherence. [source: KARE; check-in order is synthesis]
• Example language (illustrative): "Today we'll look at one situation that puts you at risk of drinking, and one thing that would make life without alcohol worth having."
• Watch for: sessions drifting into general counselling. Use the guidebook. Working: the client links both themes to their own life.

E2. Identifying and managing high-risk situations

• Purpose / when: relapse-prevention theme. [source: KARE]
• Steps: (1) List the people, places, emotions and times linked to drinking. (2) Rank them by risk. (3) For each, plan avoidance or coping (leave, call someone, use a skill). (4) Rehearse the plan. [source: technique named in KARE; steps are standard relapse prevention, synthesis]
• Example language (illustrative): "When is the urge strongest? Let's plan exactly what you'll do the next time you're in that situation."
• Watch for: vague plans. Working: specific plans used and reported in the journal.

E3. Urge surfing

• Purpose / when: craving management. [source: KARE]
• Steps: (1) Notice the urge without acting. (2) Locate it in the body. (3) Observe it rising, peaking and subsiding like a wave, using the breath as an anchor. (4) Note that it passes. (5) Practise at home. [source: named in KARE; steps standard MBRP, synthesis]
• Example language (illustrative): "Where do you feel the craving right now? Just watch it, like a wave, and notice whether it changes."
• Watch for: the client using the exercise to suppress the urge. Working: urges ride out without drinking.

E4. Mindfulness and relaxation practices

• Purpose / when: one exercise per session, also used as the coping tool during drug sessions. [source: KARE]
• Steps: (1) Introduce the practice (for example breath awareness, body scan, progressive relaxation; the specific exercises were not listed in the source, uncertain). (2) Guide it in session. (3) Debrief the experience. (4) Assign daily practice. [source: KARE; examples are synthesis]
• Example language (illustrative): "Let's try ten minutes of noticing the breath. Whenever your mind wanders, just bring it back, without judging."
• Watch for: distress or dissociation during practice (see 5.8). Working: regular home practice and use during cravings.

E5. Activity scheduling for a meaningful life

• Purpose / when: wellbeing theme. [source: KARE]
• Steps: (1) Identify enjoyable and valued non-drinking activities. (2) Schedule them, especially at high-risk times. (3) Review the effect on mood and urges. [source: named in KARE; steps synthesis]
• Example language (illustrative): "Friday evenings used to be the pub. What could fill that slot that you'd actually look forward to?"
• Watch for: activities that bring back drinking cues.

E6. Problem solving

• Purpose / when: practical stressors that drive drinking. [source: KARE]
• Steps: (1) Define the problem. (2) Brainstorm options. (3) Weigh pros and cons. (4) Choose and plan. (5) Review the outcome. [steps: standard problem-solving, synthesis]
• Example language (illustrative): "Let's write down every possible option, even silly ones, before we judge any of them."
• Watch for: avoidance of the actual problem.

E7. Addressing thinking biases (CBT-based)

• Purpose / when: permission-giving or catastrophic thoughts about drinking. [source: KARE]
• Steps: (1) Identify the thought (e.g. "one won't hurt"). (2) Name the bias. (3) Examine the evidence and consequences. (4) Form an alternative response. [steps synthesis]
• Example language (illustrative): "What does that 'just one' thought usually lead to, based on your experience?"

E8. Journals and between-session exercises

• Purpose / when: throughout. [source: KARE]
• Steps: (1) The client logs urges, situations, coping and mindfulness practice. (2) The client reflects on the resources needed for a life without alcohol. (3) Review at the next session.
• Watch for: blank journals. Simplify the format. [synthesis]

E9. Bracketing the drug session (KARE-specific)

• Purpose / when: each drug session is bracketed by a therapy session before and one the following day. [source: KARE]
• Steps: see A3 (preparation, intention), A4 (presence), A5 (next-day integration). In the control arms the same contact took the form of alcohol education (addiction drivers, biological effects of alcohol, healthy living and nutrition), deliberately without relapse prevention, mindfulness or wellbeing work. [source: KARE]

F1. Agreeing the abstinence start day (MET platform)

• Purpose / when: first week of the NYSPI protocol. [source: NCT02539511]
• Steps: (1) Discuss readiness. (2) Agree with the client an abstinence start day, timed by the protocol relative to the drug session. (3) Plan support and withdrawal safety with the medical team (inability to start abstinence safely was an exclusion). [source: NCT02539511]
• Example language (illustrative): "Which day this coming week feels realistic to stop? What will you need in place?"
• Watch for: withdrawal risk (medical team assesses). Working: the client arrives sober and not in withdrawal.

F2. MET goal-setting session

• Purpose / when: initial MET session. [source: NCT02539511]
• Steps: (1) Explore the client's own goals for drinking. (2) Explore ambivalence: what drinking gives and costs. (3) Elicit and reflect the client's own motivational (change) statements. (4) Summarise and strengthen commitment. [source: goal setting, ambivalence and motivational statements named in NCT02539511; reflective style is standard MET, synthesis] Personalised feedback, decisional balance and a written change plan are standard MET components but were not specified in the protocol [uncertain].
• Example language (illustrative): "What would be different for you if alcohol played a smaller part in your life?" / "So part of you enjoys the evenings out, and part of you is worried about your liver."
• Watch for: the therapist arguing for change (it evokes counter-arguments). Working: the client voices more change talk than sustain talk.

F3. MET follow-up sessions

• Purpose / when: 2–4 follow-ups across the 5 weeks. [source: NCT02539511]
• Steps: (1) Review drinking (timeline follow-back) and progress toward the goal. (2) Reflect and reinforce change talk. (3) Revisit ambivalence when lapses occur. (4) Strengthen self-efficacy. [synthesis from standard MET]
• Example language (illustrative): "You managed four days without drinking. What helped you do that?"

F4. Mindfulness-based relaxation before and during the drug session (MBRP-derived)

• Purpose / when: drug-session day, before and during, delivered by a trained sitter. [source: NCT02539511, exercises drawn from the MBRP manual]
• Steps: see A3/A4. Guide brief relaxation and mindful breathing. Give psychological preparation about what may occur.

F5. Post-drug-session MET session (before discharge)

• Purpose / when: the drug-session day, after the acute effects have subsided and before medical discharge. [source: NCT02539511]
• Steps: (1) Brief check on the experience. (2) Connect it to the client's reasons for change. (3) Elicit commitment statements and next steps. (4) Confirm the plan until the next visit. [steps 2–4 synthesis]
• Example language (illustrative): "After today, how important does changing your drinking feel, and what's your next step?"
• Watch for: residual effects. Discharge readiness is the physician's decision after psychiatric evaluation. [source: NCT02539511]

5. Handling problems

Tags: [source] = from an opened protocol; [synthesis] = my own guidance from general practice in the host therapies.

5.1 Clinical deterioration or rising suicidality. Serious adverse events in the Yale CBT trial were worsening depression or suicidality, in both arms. [source: Wilkinson 2021] The VA protocol defines review triggers (25% rise on PCL-5/CAPS-5, CGI ≥6, increased suicidality) that lead to full investigator assessment. [source: NCT04560660] Response: run a structured risk assessment (C-SSRS) when scores rise, notify the prescriber the same day, update a written safety plan, and discuss lethal-means safety (storage and removal) with the client and family. Continue therapy unless the team decides otherwise. [synthesis, following standard risk practice]

5.2 Return of symptoms when ketamine stops (the "cliff"). This is the problem these pairings target. Gains faded after the 2-week EX/RP window. [source: Rodriguez 2016; Wilkinson 2021 rationale] Response: name the risk at the start. Front-load skills while the client feels better. Frame later sessions as the main event. Normalise dips as a return of old patterns to work on, not proof of failure. Plan continuation therapy before the paired phase ends. [synthesis]

5.3 "The drug did it": low engagement with therapy. Response: acknowledge the relief, then ask what the client has done differently since. Link each gain to a skill. Use the client's own data (activity chart, SUDS trend). Remind them that the trial designs exist because drug effects alone often fade. [synthesis; rationale from Wilkinson 2021]

5.4 Avoidance of exposure (EX/RP, PE). Response: revisit the rationale, step down the hierarchy one level, use shorter and more frequent exposures, and identify safety behaviours. For PE, pilot interviews linked dropout to worsening symptoms and low confidence about coping with symptom flare-ups. Pre-warn that symptoms can rise temporarily early in exposure, and agree a coping plan. [source: dropout finding in NCT04560660; responses synthesis]

5.5 Under- or over-engagement in imaginal exposure. Under-engagement: ask for present tense, eyes closed, sensory detail and more frequent SUDS. Over-engagement or dissociation: eyes open, past tense, ground in the room (say the date, name objects), shorten the segment, then resume. [synthesis: standard PE practice; not detailed in the opened protocols, uncertain]

5.6 Homework non-adherence. Response: review homework first every session (B2). Explore the barrier without judgement. Shrink the task. Schedule a specific time. Do the first part in session. In addiction pairings, use the journal as a brief daily log, not an essay. [source: homework review in Wilkinson 2021, KARE journals; responses synthesis]

5.7 Ambivalence and resistance (MET, KARE). Response: roll with it. Reflect both sides. Avoid arguing for change. Return to the client's own goals and their intention for life without alcohol. Elicit the client's own change statements. [source: MET focus on ambivalence and motivational statements, NCT02539511; KARE intention; style synthesis]

5.8 Distress during the drug session. Panic, fear, paranoid thoughts or confusion. Response: brief reassurance, return to the practised breathing or mindfulness skill, reduce stimulation. Alert medical staff immediately. The physician decides on stopping and on further care. [source: therapist present for reassurance in KARE; physician decides discontinuation in NCT02539511; responses synthesis] Do not start therapeutic exploration during the acute phase. [source: NCT04560660]

5.9 Persistent dissociation, psychotic symptoms, mania or euphoria afterwards. NYSPI removed and referred participants with psychosis or persistent dissociation. The VA protocol rated dissociation, psychotomimetic and mania symptoms. KARE recorded severe low mood and euphoria as adverse events. [source: NCT02539511; NCT04560660; KARE] Response: report to the prescriber at once. Postpone exposure or demanding work until the client is stable. Document. [synthesis]

5.10 Physical adverse effects (e.g. raised blood pressure, fast heart rate). These are medical-team matters (KARE recorded hypertension and tachycardia as severe events). The therapist reports what the client tells them and does not advise on them. [source: KARE; NCT02539511]

5.11 Arriving intoxicated, in withdrawal, or after a lapse (alcohol pairings). Response: do not proceed with the drug session. The protocol reschedules (NYSPI: within a week; withdrawal above threshold on the day was a discontinuation trigger). Treat the lapse as learning: do a functional analysis of the high-risk situation and update the coping plan. [source: NCT02539511; KARE abstinence gate; lapse response synthesis]

5.12 Ketamine misuse or wanting more ketamine. Six KARE participants reported one recreational ketamine use during follow-up. [source: KARE] Response: ask routinely and without judgement. Explore the function it serves (relief, curiosity, chasing the experience). Inform the prescriber within the confidentiality limits agreed at consent. Treat it in the therapy as you would any substance use. Give general harm-reduction information about risks such as accidents, dependence and bladder problems with repeated use (general knowledge, not from the sources) [synthesis] [uncertain].

5.13 Ruptures: the client feels the therapist is "less important" than the drug, or feels handed between team members. Response: name the team structure openly. Keep one primary therapist across all sessions where possible (Columbia used a single therapist; KARE therapists delivered every session). Invite feedback each session. Repair by acknowledging missteps. [source: single-therapist delivery in Rodriguez 2016 and KARE; repair steps synthesis]

5.14 Fatigue and overload in massed formats. Response: check energy at the start of each day, keep breaks, and keep homework achievable. Follow-up calls were built into the Yale design. [source: NCT02727998 follow-up contacts; rest synthesis]

5.15 Expectancy and blinding in trials. Clients may guess their arm (active ketamine produces noticeable effects). Response: tell clients the therapy is the same in every arm and that their effort in it matters regardless. Never speculate about allocation; unblinding goes through the PI and pharmacist. [source: unblinding procedure NCT04560660; response synthesis]

5.16 Clients receiving ketamine from outside clinics (no team structure). Response: assess the indication, the prescriber, the setting and the screening received. Ask for written consent to contact the prescriber and agree roles. Screen for the exclusions in Section 2 and raise any concerns with the prescriber. Offer the host therapy (CBT, ERP, PE, MBRP, MET) on its own merits. Give general risk education (do not drive afterwards, avoid mixing with alcohol or sedatives, get medical review for side effects) without dosing advice. If use is illicit or unsupervised, the role is harm reduction, safety planning and referral, never facilitation or sourcing. [synthesis; REMS setting requirement from CBH document]

5.17 Telehealth sessions. The VA protocol allowed PE by VA video or phone. [source: NCT04560660] Never conduct a telehealth session while the client is under acute drug effects. Confirm location and an emergency contact at every telehealth session. [synthesis]

5.18 Therapist role drift (being asked to manage medical matters). Response: refer every medical question (drug sessions, side effects, interactions, discharge) back to the prescriber. Keep a written role agreement. [source: role division across protocols; synthesis]

Sources

Sources:

• Wilkinson et al. 2021, Cognitive Behavioral Therapy to Sustain the Antidepressant Effects of Ketamine in Treatment-Resistant Depression, Psychother Psychosom 90(5):318–327 (Ovid)
• Yale School of Medicine news: CBT after esketamine can prevent relapses (CBT-ENDURE)
• Rodriguez CI et al. 2016, letter on exposure-based CBT to extend ketamine's effects in OCD, J Clin Psychiatry 77(3):408–409
• NCT04560660 protocol and SAP: Ketamine-enhanced Prolonged Exposure Therapy in PTSD (Minneapolis VA)
• NCT02727998 protocol and SAP: Intensive 7-day treatment for PTSD combining ketamine with exposure therapy (Yale)
• Grabski M, McAndrew A, Lawn W, … Morgan CJA, Ketamine adjunctive to relapse prevention-based psychological therapy for alcohol use disorder (KARE), author manuscript, UCL Discovery. Journal and year are not stated in the text; the repository filename suggests Am J Psychiatry [uncertain].
• ISRCTN85955128, MORE-KARE phase III trial record (PDF)
• NCT02539511 protocol: Glutamatergic Modulation of Disordered Alcohol Use (Dakwar, NYSPI)
• Community Behavioral Health (Philadelphia), Spravato procedures, Oct 2025
• Pharmaceutical Journal, Rapid-acting antidepressants face a slow journey to wider use, Sept 2023

Further reading (not drawn on; cited only as noted): Wilkinson ST et al. 2017, pilot of CBT to sustain ketamine's antidepressant effects in treatment-resistant depression, Psychother Psychosom 86(3):162–7; NCT03027362 record (page did not render); Healio, FDA approves Spravato as monotherapy, Jan 2025.

Further reading (not drawn on): books cited: Foa EB, Yadin E, Lichner TK (2012). Exposure and Response (Ritual) Prevention for Obsessive-Compulsive Disorder: Therapist Guide, 2nd ed. Foa EB, Hembree EA, Rothbaum BO (2007; 2nd ed. 2019). Prolonged Exposure Therapy for PTSD: Therapist Guide. Bowen S, Chawla N, Marlatt GA (2011). Mindfulness-Based Relapse Prevention for Addictive Behaviors: A Clinician's Guide. Miller WR, Zweben A, DiClemente CC, Rychtarik RG (1992). Motivational Enhancement Therapy Manual (Project MATCH). Beck JS (2011). Cognitive Behavior Therapy: Basics and Beyond, 2nd ed. [uncertain: book editions from general knowledge, not verified]